Dataset Information

Preclinical PET Imaging of NTSR-1-Positive Tumors with ⁶⁴Cu- and ⁶⁸Ga-DOTA-Neurotensin Analogs and Therapy with an ²²⁵Ac-DOTA-Neurotensin Analog.

ABSTRACT: Background: The aim of the study was to perform PET imaging and radiotherapy with a novel neurotensin derivative for neurotensin receptor 1 (NTSR-1)-positive tumors in an animal model. Materials and Methods: A di-DOTA analog of NT(6-13) with three unnatural amino acids was synthesized and radiolabeled with either ⁶⁴Cu or ⁶⁸Ga and tested for serum stability and tumor imaging in mice bearing NTSR-1-positive PC3, and HT29 xenografts. A dose-response therapy study was performed with 18.5, 37, and 74 kBq of ²²⁵Ac-di-DOTA-α,ɛ-Lys-NT(6-13). Results: ⁶⁸Ga-di-DOTA-α,ɛ-Lys-NT(6-13) was >99% stable in serum for 48 h, had an IC₅₀ of 5 nM using ¹²⁵I labeled NT(8-13) for binding to HT-29 cells, and high uptake in tumor models expressing NTSR-1. ⁶⁸Ga-di-DOTA-α,ɛ-Lys-NT(6-13) had an average %ID/g (n = 4) at 2 h of 4.0 for tumor, 0.5 for blood, 12.0 for kidney, and <1 for other tissues, resulting in a favorable T/B of 8. Mean survivals of tumor-bearing mice treated with 18.5 or 37 kBq of ²²⁵Ac-di-DOTA-α,ɛ-Lys-NT(6-13) were 81 and 93 d, respectively, versus 53 d for controls. Whole-body toxicity was seen for the 74 kBq dose. Conclusions: Based on the results of the animal model, di-DOTA-α,ɛ-Lys-NT(6-13) is a useful imaging agent for NTSR-1-positive tumors when radiolabeled with ⁶⁸Ga, and when radiolabeled with ²²⁵Ac, a potent therapeutic agent.

SUBMITTER: Li D

PROVIDER: S-EPMC8817734 | biostudies-literature | 2021 Oct

REPOSITORIES: biostudies-literature

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Preclinical PET Imaging of NTSR-1-Positive Tumors with 64Cu- and 68Ga-DOTA-Neurotensin Analogs and Therapy with an 225Ac-DOTA-Neurotensin Analog.

Li Daneng D Minnix Megan M Allen Rebecca R Bading James J Chea Junie J Wong Patty P Bowles Nicole N Poku Erasmus E Shively John E JE

Cancer biotherapy & radiopharmaceuticals 20200819 8

Background: The aim of the study was to perform PET imaging and radiotherapy with a novel neurotensin derivative for neurotensin receptor 1 (NTSR-1)-positive tumors in an animal model. Materials and Methods: A di-DOTA analog of NT(6-13) with three unnatural amino acids was synthesized and radiolabeled with either 64Cu or 68Ga and tested for serum stability and tumor imaging in mice bearing NTSR-1-positive PC3, and HT29 xenografts. A dose-response ...[more]

PMID: 32822229

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Project description:PurposeIn the characterization of severe lung diseases, early detection of specific inflammatory cells could help to monitor patients' response to therapy and increase chances of survival. Macrophages contribute to regulating the resolution and termination of inflammation and have increasingly been of interest for targeted therapies. [68Ga]Ga-DOTA-TATE is an established clinical radiopharmaceutical targeting somatostatin receptor subtype 2 (SSTR 2). Since activated macrophages (M1) overexpress SSTR 2, the aim of this study was to investigate the applicability of [68Ga]Ga-DOTA-TATE for positron emission tomography (PET) imaging of M1 macrophages in pulmonary inflammation.MethodsInflammation in the pig lungs was induced by warm saline lavage followed by injurious ventilation in farm pigs (n = 7). Healthy pigs (n = 3) were used as control. A 60-min dynamic PET scan over the lungs was performed after [68Ga]Ga-DOTA-TATE injection and [18F]FDG scan was executed afterward for comparison. The uptake of both tracers was assessed as mean standardized uptake values (SUVmean) 30-60-min post-injection. The PET scans were followed by computed tomography (CT) scans, and the Hounsfield units (HU) were quantified of the coronal segments. Basal and apical segments of the lungs were harvested for histology staining. A rat lung inflammation model was also studied for tracer specificity using lipopolysaccharides (LPS) by oropharyngeal aspiration. Organ biodistribution, ex vivo autoradiography (ARG) and histology samples were conducted on LPS treated, octreotide induced blocking and control healthy rats.ResultsThe accumulation of [68Ga]Ga-DOTA-TATE on pig lavage model was prominent in the more severely injured dorsal segments of the lungs (SUVmean = 0.91 ± 0.56), compared with control animals (SUVmean = 0.27 ± 0.16, p < 0.05). The tracer uptake corresponded to the damaged areas assessed by CT and histology and were in line with HU quantification. The [68Ga]Ga-DOTA-TATE uptake in LPS treated rat lungs could be blocked and was significantly higher compared with control group.ConclusionThe feasibility of the noninvasive assessment of tissue macrophages using [68Ga]Ga-DOTA-TATE/PET was demonstrated in both porcine and rat lung inflammation models. [68Ga]Ga-DOTA-TATE has a great potential to be used to study the role and presence of macrophages in humans in fight against severe lung diseases.

Project description:BackgroundSince it was first approved in Europe in 2016, the gallium-68 (68Ga) radiopharmaceutical [68Ga]Ga-DOTA-TOC has been widely used for imaging of somatostatin receptor (SSTR) positive tumours using positron emission tomography-computed tomography (PET/CT). Significant patient benefits have been reported, so its use is rapidly increasing. However, few studies have been published regarding occupational doses to nuclear medicine personnel handling this radiopharmaceutical, despite its manual usage at low distances from the skin and the beta-emission decay scheme, which may result in an increased absorbed dose to their hands. In this context, this study aims to analyse the occupational exposure during the administration of [68Ga]Ga-DOTA-TOC for PET/CT imaging. For this purpose, extremity, eye lens and whole-body dosimetry in terms of Hp(0.07), Hp(3) and Hp(10), respectively, was conducted on six workers with both thermoluminescent dosimeters, and personal electronic dosimeters.ResultsThe non-dominant hand is more exposed to radiation than the dominant hand, with the thumb and the index fingertip being the most exposed sites on this hand. Qualitative analysis showed that when no shielding is used during injection, doses increase significantly more in the dominant than in the non-dominant hand, so the use of shielding is strongly recommended. While wrist dosimeters may significantly underestimate doses to the hands, placing a ring dosimeter at the base of the ring or middle finger of the non-dominant hand may give a valuable estimation of maximum doses to the hands if at least a correction factor of 5 is applied. Personal equivalent doses for the eyes did not result in measurable values (i.e., above the lowest detection limit) for almost all workers. The extrapolated annual dose estimations showed that there is compliance with the annual dose limits during management of [68Ga]Ga-DOTA-TOC for diagnostics with PET in the hospital included in this study.ConclusionsImaging with [68Ga]Ga-DOTA-TOC is a safe process for the workers performing the administration of the radiopharmaceutical, including intravenous injection to the patient and the pre- and post-activity control, as it is highly unlikely that annual dose limits will be exceeded if good working practices and shielding are used.

Project description:BackgroundThe [177Lu]Lu-DOTA-TATE mediated peptide receptor radionuclide therapy (PRRT) of neuroendocrine tumors (NETs) is sometimes leading to treatment resistance and disease recurrence. An interesting alternative could be the somatostatin antagonist, [177Lu]Lu-DOTA-JR11, that demonstrated better biodistribution profile and higher tumor uptake than [177Lu]Lu-DOTA-TATE. Furthermore, treatment with alpha emitters showed improvement of the therapeutic index of PRRT due to the high LET offered by the alpha particles compared to beta emitters. Therefore, [225Ac]Ac-DOTA-JR11 can be a potential candidate to improve the treatment of NETs (Graphical abstract). DOTA-JR11 was radiolabeled with [225Ac]Ac(NO3)3 and [177Lu]LuCl3. Stability studies were performed in phosphate buffered saline (PBS) and mouse serum. In vitro competitive binding assay has been carried out in U2OS-SSTR2 + cells for natLa-DOTA-JR11, natLu-DOTA-JR11 and DOTA-JR11. Ex vivo biodistribution studies were performed in mice inoculated with H69 cells at 4, 24, 48 and 72 h after injection of [225Ac]Ac-DOTA-JR11. A blocking group was included to verify uptake specificity. Dosimetry of selected organs was determined for [225Ac]Ac-DOTA-JR11 and [177Lu]Lu-DOTA-JR11.Results[225Ac]Ac-DOTA-JR11 has been successfully prepared and obtained in high radiochemical yield (RCY; 95%) and radiochemical purity (RCP; 94%). [225Ac]Ac-DOTA-JR11 showed reasonably good stability in PBS (77% intact radiopeptide at 24 h after incubation) and in mouse serum (~ 81% intact radiopeptide 24 h after incubation). [177Lu]Lu-DOTA-JR11 demonstrated excellent stability in both media (> 93%) up to 24 h post incubation. Competitive binding assay revealed that complexation of DOTA-JR11 with natLa and natLu did not affect its binding affinity to SSTR2. Similar biodistribution profiles were observed for both radiopeptides, however, higher uptake was noticed in the kidneys, liver and bone for [225Ac]Ac-DOTA-JR11 than [177Lu]Lu-DOTA-JR11.Conclusion[225Ac]Ac-DOTA-JR11 showed a higher absorbed dose in the kidneys compared to [177Lu]Lu-DOTA-JR11, which may limit further studies with this radiopeptide. However, several strategies can be explored to reduce nephrotoxicity and offer opportunities for future clinical investigations with [225Ac]Ac-DOTA-JR11.

Project description:The trend to inform personalized molecular radiotherapy with molecular imaging diagnostics, a concept referred to as theranostics, has transformed the field of nuclear medicine in recent years. The development of theranostic pairs comprising somatostatin receptor (SSTR)-targeting nuclear imaging probes and therapeutic agents for the treatment of patients with neuroendocrine tumors (NETs) has been a driving force behind this development. With the Neuroendocrine Tumor Therapy (NETTER-1) phase 3 trial reporting encouraging results in the treatment of well-differentiated, metastatic midgut NETs, peptide radioligand therapy (RLT) with the 177Lu-labeled somatostatin analog (SSA) [177Lu]Lu-DOTA-TATE is now anticipated to become the standard of care. On the diagnostics side, the field is currently dominated by 68Ga-labeled SSAs for the molecular imaging of NETs with positron emission tomography-computed tomography (PET/CT). PET/CT imaging with SSAs such as [68Ga]Ga-DOTA-TATE, [68Ga]Ga-DOTA-TOC, and [68Ga]Ga-DOTA-NOC allows for NET staging with high accuracy and is used to qualify patients for RLT. Driven by the demand for PET/CT imaging of NETs, a commercial kit for the production of [68Ga]Ga-DOTA-TATE (NETSPOT) was approved by the U.S. Food and Drug Administration (FDA). The synthesis of 68Ga-labeled SSAs from a 68Ge/68Ga-generator is straightforward and allows for a decentralized production, but there are economic and logistic difficulties associated with these approaches that warrant the search for a viable, generator-independent alternative. The clinical introduction of an 18F-labeled SSTR-imaging probe can help mitigate the shortcomings of the generator-based synthesis approach, but despite extensive research efforts, none of the proposed 18F-labeled SSAs has been translated past prospective first-in-humans studies so far. Here, we review the current state of probe-development from a translational viewpoint and make a case for a clinically viable, 18F-labeled alternative to the current standard [68Ga]Ga-DOTA-TATE.

Project description:This is the initial report of an α-based pre-targeted radioimmunotherapy (PRIT) using 225Ac and its theranostic pair, 111In. We call our novel tumor-targeting DOTA-hapten PRIT system "proteus-DOTA" or "Pr." Herein we report the first results of radiochemistry development, radiopharmacology, and stoichiometry of tumor antigen binding, including the role of specific activity, anti-tumor efficacy, and normal tissue toxicity with the Pr-PRIT approach (as α-DOTA-PRIT). A series of α-DOTA-PRIT therapy studies were performed in three solid human cancer xenograft models of colorectal cancer (GPA33), breast cancer (HER2), and neuroblastoma (GD2), including evaluation of chronic toxicity at ~20 weeks of select survivors. Methods: Preliminary biodistribution experiments in SW1222 tumor-bearing mice revealed that 225Ac could not be efficiently pretargeted with current DOTA-Bn hapten utilized for 177Lu or 90Y, leading to poor tumor uptake in vivo. Therefore, we synthesized Pr consisting of an empty DOTA-chelate for 225Ac, tethered via a short polyethylene glycol linker to a lutetium-complexed DOTA for picomolar anti-DOTA chelate single-chain variable fragment (scFv) binding. Pr was radiolabeled with 225Ac and its imaging surrogate, 111In. In vitro studies verified anti-DOTA scFv recognition of [225Ac]Pr, and in vivo biodistribution and clearance studies were performed to evaluate hapten suitability and in vivo targeting efficiency. Results: Intravenously (i.v.) administered 225Ac- or 111In-radiolabeled Pr in mice showed rapid renal clearance and minimal normal tissue retention. In vivo pretargeting studies show high tumor accumulation of Pr (16.71 ± 5.11 %IA/g or 13.19 ± 3.88 %IA/g at 24 h p.i. for [225Ac]Pr and [111In]Pr, respectively) and relatively low uptake in normal tissues (all average ≤ 1.4 %IA/g at 24 h p.i.). Maximum tolerated dose (MTD) was not reached for either [225Ac]Pr alone or pretargeted [225Ac]Pr at administered activities up to 296 kBq/mouse. Single-cycle treatment consisting of α-DOTA-PRIT with either huA33-C825 bispecific anti-tumor/anti-DOTA-hapten antibody (BsAb), anti-HER2-C825 BsAb, or hu3F8-C825 BsAb for targeting GPA33, HER2, or GD2, respectively, was highly effective. In the GPA33 model, no complete responses (CRs) were observed but prolonged overall survival of treated animals was 42 d for α-DOTA-PRIT vs. 25 d for [225Ac]Pr only (P < 0.0001); for GD2, CRs (7/7, 100%) and histologic cures (4/7, 57%); and for HER2, CRs (7/19, 37%) and histologic cures (10/19, 56%) with no acute or chronic toxicity. Conclusions: [225Ac]Pr and its imaging biomarker [111In]Pr demonstrate optimal radiopharmacologic behavior for theranostic applications of α-DOTA-PRIT. For this initial evaluation of efficacy and toxicity, single-cycle treatment regimens were performed in all three systems. Histologic toxicity was not observed, so MTD was not observed. Prolonged overall survival, CRs, and histologic cures were observed in treated animals. In comparison to RIT with anti-tumor IgG antibodies, [225Ac]Pr has a much improved safety profile. Ultimately, these data will be used to guide clinical development of toxicity and efficacy studies of [225Ac]Pr, with the goal of delivering massive lethal doses of radiation to achieve a high probability of cure without toxicity.

Project description:BackgroundPancreatic ductal adenocarcinoma (PDAC) is an aggressive malignancy which may benefit from radioimmunotherapy. Previously, [177Lu]Lu-DOTA-C595 has been developed as a beta-emitting radioimmunoconjugate to target cancer-specific mucin 1 epitopes (MUC1-CE) overexpressed on PDAC. However, the therapeutic effect may be enhanced by using an alpha-emitting radionuclide such as Actinium-225 (Ac-225). The short range and high linear energy transfer of alpha particles provides dense cellular damage and can overcome typical barriers related to PDAC treatment such as hypoxia. Despite the added cytotoxicity of alpha-emitters, their clinical implementation can be complicated by their complex decay chains, recoil energy and short-range impeding radiation detection. In this study, we developed and evaluated [225Ac]Ac-DOTA-C595 as an alpha-emitting radioimmunotherapy against PDAC using a series of in vitro experiments and conducted a preliminary dosimetric assessment and cross-calibration of detectors for the clinical implementation of Ac-225.ResultsCell binding and internalisation of [225Ac]Ac-DOTA-C595 was rapid and greatest in cells with strong MUC1-CE expression. Over 99% of PDAC cells had positive yH2AX expression within 1 h of [225Ac]Ac-DOTA-C595 exposure, suggesting a high level of DNA damage. Clonogenic assays further illustrated the cytotoxicity of [225Ac]Ac-DOTA-C595 in a concentration-dependent manner. At low concentrations of [225Ac]Ac-DOTA-C595, cells with strong MUC1-CE expression had lower cell survival than cells with weak MUC1-CE expression, yet survival was similar between cell lines at high concentrations irrespective of MUC1-CE expression. A dosimetric assessment was performed to estimate the dose-rate of 1 kBq of [225Ac]Ac-DOTA-C595 with consideration to alpha particles. Total absorption of 1 kBq of Ac-225 was estimated to provide a dose rate of 17.5 mGy/h, confirmed via both detector measurements and calculations.Conclusion[225Ac]Ac-DOTA-C595 was shown to target and induce a therapeutic effect in MUC1-CE expressing PDAC cells.

Dataset Information

Preclinical PET Imaging of NTSR-1-Positive Tumors with ⁶⁴Cu- and ⁶⁸Ga-DOTA-Neurotensin Analogs and Therapy with an ²²⁵Ac-DOTA-Neurotensin Analog.

Publications

Preclinical PET Imaging of NTSR-1-Positive Tumors with <sup>64</sup>Cu- and <sup>68</sup>Ga-DOTA-Neurotensin Analogs and Therapy with an <sup>225</sup>Ac-DOTA-Neurotensin Analog.

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